Abstract
The mechanisms of airway allergen sensing and type 2 immune response initiation remain poorly understood. Using a mouse house dust mite (HDM)-induced allergic airway model, we identify a population of lung macrophages located close to alveolar capillaries that express Ly6G and the nuclear receptor Nr4a1/Nur77. These atypical Ly6G+Nur77+ macrophages preferentially capture airway-delivered allergens and play an important role in initiating HDM-driven T helper type 2 (Th2) responses. They sense the major HDM allergen, the cysteine protease Der p 1, via protease-activated receptor 2 (PAR2), and their activation and accumulation require both PAR2 and Nr4a1/Nur77. These Ly6G+Nur77+ macrophages regulate the migration of conventional migratory dendritic cells (mDCs) to draining mediastinal lymph nodes (mLNs) through cysteinyl leukotriene (CysLT) production, which enhances mDC migration toward CCL21 for T cell priming. Inhibiting CysLT biosynthesis reduces mDC migration and dampens Th2 allergic responses, highlighting possible therapeutic avenues in type 2 immunity.
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Data availability
RNA-seq data have been deposited in the Gene Expression Omnibus (GEO) under accession GSE291081, and scRNA-seq data have been deposited in GEO under accessions GSE289548 and GSE305119 and are publicly available. Any additional information required to reanalyze the data reported in this paper is available from the corresponding author upon request. All other data are available in the article and its Supplementary files or from the corresponding author upon request. Source data are provided with this paper.
Code availability
The code used to analyze the scRNA-seq data can be accessed at https://doi.org/10.5281/zenodo.15149503 and https://doi.org/10.5281/zenodo.16848446.
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Acknowledgements
We thank Dr. Catherine C. Hedrick (Augusta University, Augusta, GA, USA), Pamela A. Frischmeyer-Guerrerio, Karen Laky, and Justin Lack (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA) for providing mice and bioinformatics support. We also thank Becca Burnham, Kelsey Browning, and Thomas ‘Scott’ Simpler (University of Alabama at Birmingham, Birmingham, AL, USA) for animal husbandry, and the UAB FCSC Core for assistance with cell sorting and preparation of scRNA-seq libraries. This work utilized the computational resources of the NIH HPC Biowulf cluster (https://hpc.nih.gov). This research was supported in part by National Institutes of Health (NIH) grant 2R01AI116584 to BL, and by the Intramural Research Program of the NIH. The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.
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Conceptualization, A.M. and B.L.; Methodology, A.M., H.B., C.L., S.D., G.P., J.C.G., and B.L.; Formal analysis, A.M., B.D., D.D.H., P.L., A.F.R., and B.L.; Visualization, A.M., B.D., and B.L.; Writing – original draft, A.M. and B.L.; Writing – review and editing, B.L.; Supervision, B.L.; Funding acquisition, B.L.
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Meloun, A., Bachus, H., Lewis, C. et al. Atypical pericapillary Ly6G⁺Nur77⁺ macrophages initiate type-2 immune responses to allergens in the mouse lung. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68652-5
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DOI: https://doi.org/10.1038/s41467-026-68652-5
